The present invention relates to new indole derivatives, a process for producing them and their use to prepare valuable compounds.
Carboline derivatives, especially substituted .beta.-carboline derivatives, have recently aroused great interest in pharmacological research since they exert a wealth of therapeutically useful effects on the central nervous system. For example, they display anticonvulsive, anxiolytic, muscle relaxing and/or sedative effects.
The importance that is given to this class of substances is further reflected in the great number of patent applications filed, of which the following are examples: DE-OS No. 30 15 816, DE-OS No. 30 23 567, DE-OS No. 30 48 318 and U.S. Pat. No. 3,302,667.
The substituted tryptophans for example, have a sleep inducing effect. Tryptophan is widely used, for example, as an additive to infusion solutions, animal feed, etc.
The processes that are described in the literature for the production of .beta.-carbolines and tryptophan derivatives have the drawback that they go through several stages and are not always satisfactory in yields (R. A. Abramovitch and J. D. Spenser, Advances in Heterocycl. Chemistry, Vol. 3, p 79).
A typical carboline and tryptophan synthesis can be summarized by the diagram on the next page. ##STR3##
Starting with indole (1), gramine or a compound analogous to gramine (2) is produced by reaction with formaldehyde and a secondary amine. This is converted into a tryptophan precursor (3) by reaction with acetoamidomalonic ester under basic catalysis.
Racemic tryptophon (4) is formed after elimination of all protective groups and decarboxylation. Tryptophan ester (5) is formed after esterification, from which a 3,4-dihydro-.beta.-carboline (6a) is formed after acylation of the amino group and cyclization under Bischler-Napieralski reaction conditions, and a tetrahydro-.beta.-carboline (6b) is formed according to Pictet-Spengler. It is converted into the carbolines (7) after dehydration.
Apart from the large number of synthesis steps with the inevitable loss of time and yield, the cyclizations according to Bischler-Napieralski and Pictet-Spengler, cause special problems. Despite numerous improvements in these processes, only a slight yield results, whereby sensitive, partially hydrogenated intermediate products are formed which can cause various secondary reactions. Also, the dehydrogenation reaction to form di- and tetrahydrocarbolines often results in a low yield.
For this reason, it would be considered a particularly important advance in process engineering, if it were possible to perform a ring closure reaction on unsaturated indole precursors, exemplified by dehydrotryptophan derivatives, whereby a simple production process would be a prerequisite for the required dehydrotryptophan derivatives.
It would be a further important advance in process engineering, if it were possible to perform this ring closure reaction on a dehydrotryptophan derivative in such a way that the aromatic carboline system would be formed instead of a 1,2-dihydrocarboline derivative.